US4456601A - 3-Chloro-pregnane derivatives and a process for the preparation thereof - Google Patents

3-Chloro-pregnane derivatives and a process for the preparation thereof Download PDF

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Publication number
US4456601A
US4456601A US06/434,335 US43433582A US4456601A US 4456601 A US4456601 A US 4456601A US 43433582 A US43433582 A US 43433582A US 4456601 A US4456601 A US 4456601A
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United States
Prior art keywords
chloro
formula
mixture
acetonide
hydrogen
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Expired - Fee Related
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US06/434,335
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English (en)
Inventor
Jozsef Toth
Gyorgy Hajos
Gyorgy Fekete
Istvan Horvath
Laszlo Szporny
Anna Boor nee Mezei
Peter Aranyi
Aniko Naray
Sandor Gorog
Sandor Holly
Csaba Molnar
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Richter Gedeon Vegyeszeti Gyar Nyrt
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Richter Gedeon Vegyeszeti Gyar RT
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Assigned to RICHTER GEDEON VEGYESZETI GYAR RT. reassignment RICHTER GEDEON VEGYESZETI GYAR RT. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ARANYI, PETER, BOOR, ANNA, FEKETE, GYORGY, GOROG, SANDOR, HAJOS, GYORGY, HOLLY, SANDOR, HORVATH, ISTVAN, MOLNAR, CSABA, NARAY, ANIKO, SZPORNY, LASZLO, TOTH, JOZSEF
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to new 3-chloro-pregnane derivatives of the formula (I), ##STR4## wherein X is hydrogen, acetyl or chloroacetyl, and
  • Y and Z represent hydrogen or halogen, with at least one of them being other than hydrogen
  • compositions containing the same as well as to a process for the preparation thereof.
  • Iminium salts have been used increasingly wide-spread in preparative organic chemistry in the last few years [see e.g. H. Bohme and H. G. Viehe: "Iminium Salts in Organic Chemistry", with particular respect to the chapter entitled “The Vilsmeier-Haack-Arnold Acylations” (Advances in Organic Chemistry: Methods and Results, Ed.: E. C. Taylor, Vol. 9, Part 1, pp. 225-333; J. Wiley and Sons, Inc., 1976)].
  • This reaction has also been utilized in the field of steroid chemistry; thus e.g. the 3-enolethers of ⁇ 4 -3-oxo-pregnane derivatives can be treated with Vilsmeier reagents to obtain the respective 6-formyl compounds with good yields.
  • anion A.sup.(-) in the reactant influences the course of the reaction [see Tetrahedron 25, 1155 (1969)].
  • Free ⁇ 4 -3-oxo-oestrane derivatives, furthermore ⁇ 4 -3-oxo-androstane, ⁇ 4 ,6 -3-oxo-oestrane and -androstane derivatives yield variously formylated 3-chloro-steroid-dienes or -trienes in this reaction [see Tetrahedron Letters 1965, 137; Chem. Ber. 101, 2393 (1968)], 5 ⁇ -androstane-3-one derivatives convert into the respective 3-chloro-2,4-diformyl compounds under severe reaction conditions (J. Chem.
  • the invention relates to a process for the preparation of new ⁇ 1 ,3,5 -3-chloro-pregnane derivatives of the formula (I), wherein X, Y and Z are as defined above.
  • a ⁇ 1 ,4 -3-oxo-pregnane derivative of the formula (II), wherein X' is acetyl or chloroacetyl and Y and Z are as defined above is reacted with a chloromethyleneiminium salt of the formula (III), wherein A.sup.(-) represents a salt-forming anion, preferably a dichlorophosphate ion (O 2 PCl 2 ), in an aproptic solvent in the presence of a tertiary base, and, if desired, a resulting compound of the formula (I), wherein X is acetyl or chloroacetyl, is subjected to hydrolysis to obtain a compound of the formula (I) wherein X is
  • the steroids of the formula (II), used as starting substances in the process of the invention, can be prepared by subjecting the respective 21-hydroxy-steroids to selective acylation. These steroids with a free hydroxy group in position 21 are known compounds.
  • the Vilsmeier reagent of the formula (III) is prepared preferably directly in the reaction medium by reacting dimethyl formamide with phosphorous oxychloride in a dry aprotic solvent. It is preferred to use halogenated lower hydrocarbons, particularly dichloromethane and/or chloroform, as aprotic solvents.
  • the reaction according to the invention is performed preferably as follows:
  • the starting substance of the formula (II) is dissolved in a dry organic solvent, preferably in the same solvent as utilized in the preparation of the Vilsmeier reagent of the formula (III), a tertiary base, preferably pyridine or a homologue thereof, such as picoline, lutidine or collidine, is added to the solution, and the resulting mixture is added to the solution of the Vilsmeier reagent, prepared as discussed above, at a temperature between -10° C. and room temperature, preferably at -10° C. to 0° C.
  • the reagent of the formula (III) is utilized preferably in excess; 3 molar equivalents of the reagent of the formula (III) can be used for one mole of the starting pregnane derivative.
  • the reaction proceeds within a period of from 20-30 minutes to 5 hours, depending on the starting substances applied. During this period the reaction mixture is allowed to warm to room temperature.
  • the mixture is decomposed by admixing it with a base, such as aqueous potassium hydrocarbonate solution.
  • a base such as aqueous potassium hydrocarbonate solution.
  • the product is extracted with a water-immiscible organic solvent, the solution is washed until neutral, dried, and the solvent is evaporated to obtain a 3-chloro-pregnane derivative of the formula (I) wherein X is acetyl or chloroacetyl group.
  • the resulting product can be subjected to acidic or alkaline hydrolysis to obtain the respective compound of the formula (I) wherein X is hydrogen.
  • Hydrolysis is performed preferably in a solvent which is at least partially miscible with water, such as in an alcohol or in a mixture of a solvent for the steroid (e.g. benzene) and an alcohol, at a temperature between room temperature and the boiling point of the reaction mixture.
  • Alkaline hydrolysis is performed preferably with an alkali metal carbonate or hydrocarbonate
  • acid hydrolysis is performed preferably with a mineral acid, such as hydrochloric acid, sulfuric acid or perchloric acid, or an organic acid, such as formic acid, acetic acid or trifluoroacetic acid.
  • the X' acyl group of the starting substance of the formula (II) is selected preferably so that its hydrolytic splitting can be performed under optimum conditions which do not damage substituents Y and Z already present in the molecule.
  • a compound of the formula (I) wherein X is hydrogen and Y and Z stand for fluorine is to be prepared, it is preferred to use a compound of the formula (II) wherein Y and Z stand for fluorine and X' is monochloroacetyl group as starting substance, and to perform the hydrolysis under mild alkaline conditions. In this latter step the 3-chloro-21-monochloroacetoxy derivative can be dissolved e.g.
  • the reaction mixture obtained after hydrolysis can be processed in a manner known per se, e.g. by extracting the product with a water-immiscible organic solvent, washing the extract to neutral, drying, and evaporating the solvent.
  • the 3-chloro-pregnane derivatives according to the invention possess valuable glucocorticoidal effects.
  • the apparent dissociation constant of 3-chloro-TCA is 30 nM, that of fluocinolon-acetonide is 15 nM and that of 3-chloro-FCA is 25 nM, i.e. the dissociation constants of these three compounds are of the same order.
  • the apperent dissociation constant of 3-chloro-6-bromo-TCA is 60 nM.
  • TCA exerted 50% inductive effect in concentrations of 0.15 ⁇ g/mg and 0.025 ⁇ g/mg, respectively, whereas 3-chloro-TCA showed the same effect in concentrations of 0.05 mg/100 g and 0.005 mg/100 g, respectively.
  • glucocorticoids cause thymus involution [O. Greengard, R. Machovich: "Hydrocortisone Regulation of Thymidine Kinase in Thymus Involution and Hematopoietic Tissues", Biochem. Biophys. Acta 286, 382-388 (1972)], 50% reduction of thymus weight was observed on chickens with a dose of 0.01 mg/100 g and on rats with a dose of 0.001 mg/100 g for both TCA and 3-chloro-TCA.
  • the new compounds of the formula (I) can be converted into pharmaceutical compositions, such as tablets, capsules, pills, injectable solutions or suspensions, ointments, etc., according to known techniques, by utilizing conventional pharmaceutical additives (such as carriers, fillers, disintegrating aids, lubricants, coloring agents, flavoring agents, etc.).
  • conventional pharmaceutical additives such as carriers, fillers, disintegrating aids, lubricants, coloring agents, flavoring agents, etc.
  • the mixture is stirred for 20 minutes, then diluted with 200 ml of dichloromethane, and the solution is poured into an ice-cold solution of 60.9 g potassium hydrocarbonate in 1200 ml of water.
  • the mixture is stirred for 30 minutes, thereafter the phases are separated, and the aqueous phase is extracted twice with 200 ml of dichloromethane, each.
  • the organic phases are combined, washed with water, dried over anhydrous sodium sulfate, and then evaporated.
  • the residual crude product is dissolved in 200 ml of acetone, and the solution is dropped into 2 liters of ice-cold aqueous 10% sodium chloride solution.
  • IR spectrum 3580, 3450 ( ⁇ --OH), 1715 ( ⁇ >C ⁇ O, C 20 carbonyl), 1618 ( ⁇ C ⁇ C), 1055 ( ⁇ C--O, acetonide), 1382, 1373 ( ⁇ s --CH 3 , geminal methyl groups of the acetonide) cm -1 .
  • IR spectrum 3450 ( ⁇ --OH), 1771 ( ⁇ >C ⁇ O, chloroacetate), 1729 ( ⁇ >C ⁇ O, C 20 carbonyl), 1612 ( ⁇ C ⁇ C), 1378, 1360 ( ⁇ s , --CH 3 , geminal methyl groups in the acetonide), 1053 ( ⁇ --C--O--, acetonide) cm -1 .
  • 0.48 ml (5.2 mmoles) of phosphorous oxychloride is added dropwise to a mixture of 10 ml of dichloromethane and 1.53 ml of dimethyl formamide at -10° C.
  • the solution is stirred at -10° C. for 20 minutes, and then a solution of 0.9 g (1.7 mmoles) of 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ ,16 ⁇ ,17 ⁇ ,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,17-acetonide-21-monochloroacetate in a mixture of 0.02 ml of pyridine and 20 ml of dichloromethane is added.
  • the mixture is allowed to warm to room temperature, stirred at 25°-26° C. for 5 hours, then diluted with 30 ml of dichloromethane and dropped into a solution of 2.08 g (20.8 mmoles) of potassium hydrocarbonate in 100 ml of water. After 20 minutes of stirring the phases are separated, the aqueous phase is extracted three times with 30 ml of dichloromethane, each, the organic phases are combined, washed twice with 50 ml of water, each, dried over anhydrous sodium sulfate and filtered. The solvent is evaporated under reduced pressure at 30° C., the solid residue is triturated with ether, filtered off, and dried at room temperature in vacuo under protecting it from light.
  • the mixture is stirred at a temperature between -10° C. and 0° C. for one hour and then at room temperature for 4.5 hours. Thereafter the mixture is allowed to stand at 2°-5° C. for 15 hours in order to attain complete reaction.
  • the mixture is diluted with 20 ml of dichloromethane, 20 ml of a 20% aqueous sodium acetate solution are added, the mixture is stirred at room temperature for 30 minutes, and then the phases are separated.
  • the aqueous phase is extracted twice with 20 ml of dichloromethane, each, the organic phases are combined, washed with aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure.
  • the resulting suspension is stirred for one hour and then 10 ml of dichloromethane are added to it.
  • the resulting homogeneous solution is stirred for 8 hours and then dropped into 100 ml of a 1% aqueous sodium bicarbonate solution.
  • the resulting mixture is extracted three times with 50 ml of dichloromethane, each.
  • the dichloromethane solutions are combined, washed with 1% aqueous sodium bicarbonate solution and then with water until neutral, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure.
  • the crude, crystalline residue is treated with a 1:5 mixture of ether and petroleum ether, the solid is filtered off and dried in vacuo.
  • IR spectrum 3500 ( ⁇ C 21 --OH), 3440 ( ⁇ C 11 --OH), 1715 ( ⁇ >C ⁇ O, C 20 carbonyl), 1638, 1602, 1562 ( ⁇ C ⁇ C), 1382, 1375 ( ⁇ s --CH 3 , geminal methyl groups in the acetonide), 1055 ( ⁇ C--O--, acetonide) cm -1 .

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US06/434,335 1981-10-15 1982-10-14 3-Chloro-pregnane derivatives and a process for the preparation thereof Expired - Fee Related US4456601A (en)

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HU812976A HU182775B (en) 1981-10-15 1981-10-15 Process for preparing new 3-chloro-pregnane derivatives
HU2976/81 1981-10-15

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US (1) US4456601A (enrdf_load_stackoverflow)
EP (1) EP0077541B1 (enrdf_load_stackoverflow)
JP (1) JPS5899500A (enrdf_load_stackoverflow)
AT (1) ATE13676T1 (enrdf_load_stackoverflow)
AU (1) AU550441B2 (enrdf_load_stackoverflow)
CA (1) CA1202299A (enrdf_load_stackoverflow)
CS (1) CS232737B2 (enrdf_load_stackoverflow)
DD (1) DD204096A5 (enrdf_load_stackoverflow)
DE (1) DE3264070D1 (enrdf_load_stackoverflow)
HU (1) HU182775B (enrdf_load_stackoverflow)
IL (1) IL67000A0 (enrdf_load_stackoverflow)
MX (1) MX157221A (enrdf_load_stackoverflow)
PL (1) PL131232B1 (enrdf_load_stackoverflow)
SU (1) SU1181551A3 (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5565443A (en) * 1992-09-21 1996-10-15 Laboratoire Theramex S.A. Subcutaneous implants based on normegestrol derivatives
US5801165A (en) * 1992-12-24 1998-09-01 Rhone-Poulenc Rorer Limited Antiinflammatory, immunosuppressive and antialleric 16, 17-alkylidioxy-steroids

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8403905D0 (sv) * 1984-07-30 1984-07-30 Draco Ab Liposomes and steroid esters
HU203769B (en) * 1989-03-09 1991-09-30 Richter Gedeon Vegyeszet Process for producing new steroide derivatives and pharmaceutical compositions containing them

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4255331A (en) * 1978-04-05 1981-03-10 Prochem Establishment 3-Acetoxy-9β-11β-epoxy-dienes and the preparation of the corresponding 6α-halogen-4-ene-3-ones

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2990401A (en) * 1958-06-18 1961-06-27 American Cyanamid Co 11-substituted 16alpha, 17alpha-substituted methylenedioxy steroids
US2985652A (en) * 1958-06-17 1961-05-23 Syntex Sa 3-enol esters of 6-halo-16alpha-hydroxy cortical hormones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4255331A (en) * 1978-04-05 1981-03-10 Prochem Establishment 3-Acetoxy-9β-11β-epoxy-dienes and the preparation of the corresponding 6α-halogen-4-ene-3-ones

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5565443A (en) * 1992-09-21 1996-10-15 Laboratoire Theramex S.A. Subcutaneous implants based on normegestrol derivatives
US5801165A (en) * 1992-12-24 1998-09-01 Rhone-Poulenc Rorer Limited Antiinflammatory, immunosuppressive and antialleric 16, 17-alkylidioxy-steroids

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DE3264070D1 (en) 1985-07-11
DD204096A5 (de) 1983-11-16
ATE13676T1 (de) 1985-06-15
PL131232B1 (en) 1984-10-31
EP0077541B1 (de) 1985-06-05
MX157221A (es) 1988-11-04
JPH0121840B2 (enrdf_load_stackoverflow) 1989-04-24
IL67000A0 (en) 1983-02-23
PL238641A1 (en) 1983-05-23
AU8938082A (en) 1983-04-21
CS232737B2 (en) 1985-02-14
HU182775B (en) 1984-03-28
CA1202299A (en) 1986-03-25
CS736482A2 (en) 1984-06-18
EP0077541A1 (de) 1983-04-27
AU550441B2 (en) 1986-03-20
SU1181551A3 (ru) 1985-09-23
JPS5899500A (ja) 1983-06-13

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